Cell：P53触发氧化应激中的细胞坏死

缺血相关的氧化损伤往往会导致组织坏死，尤其在脑组织，局部产生的氧化应激反应较为剧烈且抗氧化损伤能力弱。因此，阐明氧化损伤的信号通路对于保护机体组织尤为重要。P53蛋白是细胞对于多种类型的损伤产生应答的中心传感器，它能在氧化应激反应中调节细胞的凋亡和自噬，但是氧化应激所导致的细胞坏死是否与P53蛋白有关目前还未有研究报道。本文研究者报道了P53能够在氧化应激中激活细胞坏死途径。

在氧化应激条件下，P53蛋白能够与线粒体基质中的亲环素D（cyclophilin D，CypD）形成复合物，使线粒体膜通透性转换孔（mitochondrial PTP pore ）打开，引起线粒体内容物释放，从而导致细胞坏死。

另外，研究人员还在中风小鼠模型的脑组织坏死区域检测到了P53-CypD复合体。阻止该复合体的形成有助于减少中风的症状。

doi:10.1016/j.cell.2012.05.014

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p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis

Angelina V. Vaseva, Natalie D. Marchenko, Kyungmin Ji, Stella E. Tsirka, Sonja Holzmann, Ute M. Moll

Ischemia-associated oxidative damage leading to necrosis is a major cause of catastrophic tissue loss, and elucidating its signaling mechanism is therefore of paramount importance. p53 is a central stress sensor responding to multiple insults, including oxidative stress to orchestrate apoptotic and autophagic cell death. Whether p53 can also activate oxidative stress-induced necrosis is, however, unknown. Here, we uncover a role for p53 in activating necrosis. In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (PTP) opening and necrosis by physical interaction with the PTP regulator cyclophilin D (CypD). Intriguingly, a robust p53-CypD complex forms during brain ischemia/reperfusion injury. In contrast, reduction of p53 levels or cyclosporine A pretreatment of mice prevents this complex and is associated with effective stroke protection. Our study identifies the mitochondrial p53-CypD axis as an important contributor to oxidative stress-induced necrosis and implicates this axis in stroke pathology.